Journal article

Publication year: 2017

Journal: European Respiratory Journal

Volume number: 49

Issue number: 2

ISSN: 0903-1936

eISSN: 1399-3003

Open access status: Bronze

DOI Link: https://doi.org/10.1183/13993003.01941-2015

Publisher: European Respiratory Society

Abstract: 

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-beta/Smad signalling. We sought to define the role of heat shock protein (HSP) 90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.

We investigated the effects of HSP90 inhibition in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis.

HSP90 expression was increased in (myo) fibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-beta 1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-beta receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90 beta interacted with TGF-beta receptor II and stabilised TGF-beta receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.

In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.

Harvard Citation style: Sibinska, Z., Tian, X., Korfei, M., Kojonazarov, B., Kolb, J., Klepetko, W., et al. (2017) Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis, European Respiratory Journal, 49(2). https://doi.org/10.1183/13993003.01941-2015

APA Citation style: Sibinska, Z., Tian, X., Korfei, M., Kojonazarov, B., Kolb, J., Klepetko, W., Kosanovic, D., Wygrecka, M., Ghofrani, H., Weissmann, N., Grimminger, F., Seeger, W., Guenther, A., & Schermuly, R. (2017). Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis. European Respiratory Journal. 49(2). https://doi.org/10.1183/13993003.01941-2015